Sirtuin 2 (SIRT2) is a member of the mammalian sirtuin (NAD+-dependent histone deacetylase) family that comprises SIRT1-7 (Houtkooper, R. H., et al., Nat. Rev. Mol. Cell Biol. 2012, 13, 225-238). SIRT2 is the only sirtuin that predominantly resides in the cytosol even though it is localized in the nucleus during mitosis. Interestingly, an alternatively spliced isoform has been reported to permanently reside in the nucleus. As the most abundant sirtuin homolog in the brain (Pandithage, R., et al., J. Cell Biol. 2008, 180, 915-929), SIRT2 has emerged as an important regulator in brain physiology and pathology (Harting, K., et al., Eur. J. Cell Biol. 2010, 89, 262-269). Several studies have suggested that selective pharmacological inhibition of SIRT2 is a promising therapeutic approach for Parkinson's disease (PD). First, overexpression of SIRT2 induced neuronal apoptosis (Pfister, J. A., et al., PLoS One 2008, 3, e4090). Second, blocking SIRT2 protected cells from the neurotoxicity induced by α-synuclein, a risk factor associated with the familial PD, in the cellular and fruit fly models of PD (Outeiro, T. F., et al., Science 2007, 317, 516-519). Third, SIRT2 exacerbated the nigrostriatal neurotoxicity induced by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) while genetic deletion (Liu, L., et al., Front. Aging Neurosci. 2014, 6, 184) or pharmacological inhibition (Chen, X., et al., PLoS One 2015, 10, e0116919) of SIRT2 prevented MPTP-induced neurodegeneration in mice. Furthermore, as a major deacetylase of α-tubulin (North, B. J., et al., Mol. Cell 2003, 11, 437-444.), SIRT2 decreased the acetylation level of microtubules, enhancing their association with pathologically mutated leucine-rich kinase 2 (LRRK2) in the Roc-COR domain (R1441C and Y1699C). While this strengthened association impaired axonal transport, genetic knockdown of SIRT2 restored both axonal transport and locomotion in fruit flies (Godena, V. K., et. al., Nat. Commun. 2014, 5, 5245).
Besides PD, blocking SIRT2 may also provide protection in other neurodegenerative diseases. First, inhibition of SIRT2 had a protective effect in a cellular model of multiple system atrophy (Hasegawa, T., et al., Neurochem. Int. 2010, 57, 857-866), which is one form of synucleinopathy like PD. Second, in the granule cells obtained from slow Wallerian degeneration (Wld(s)) mice, genetic knockdown of SIRT2 enhanced resistance to axonal degeneration while overexpression of SIRT2 abrogated the resistance (Suzuki, K., et al., Neuroscience 2007, 147, 599-612). Third, inhibiting SIRT2 offered neuroprotection in the fly, worm, and primary striatal neuron models of Huntington's disease, likely by reducing sterol biosynthesis ((a) Luthi-Carter, R., et al., Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 7927-7932; (b) Taylor, D. M., et al., ACS Chem. Biol. 2011, 6, 540-546), even though the therapeutic potential still remains to be unequivocally defined. Four, SIRT2 inhibitors have been explored for their potential therapeutic applications in the mouse models of tauopathies, such as Alzheimer's disease (AD) (Green, K. N., et al., J. Neurosci. 2008, 28, 11500-11510) and frontotemporal dementia (Spires-Jones, T. L., et al., Front. Pharmacol. 2012, 3, 42). Lastly, a neurotoxic role of SIRT2 in AD has been recently proposed ((a) Theendakara, V., et al., Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 18303-18308; (b) Silva, D. F., et al., Mol. Neurobiol. 2016, PMID: 27311773). Taken together, these studies suggest that optimized SIRT2 inhibitors will have a broad impact on the treatment of neurodegenerative diseases.
Recently, SIRT2 has been shown as a key player in the transcription regulation signalling initiated by bacterial infection, suggesting that blocking host SIRT2 may be a viable approach to fight bacterial infection (Eskandarian, H. A., et al., Science 2013, 341, 1238858). Furthermore, there are studies that suggest that SIRT2 inhibitors can be therapeutically useful in the treatment of cancer ((a) Hu, J.; Jing, H.; Lin, H., Future Med. Chem. 2014, 6, 945-966; (b) Soung, Y. H., et al., Sci. Rep. 2014, 4, 3846; (c) Jing, H., et al., Cancer Cell 2016, 29, 297; (d) Deng, A., et al., Sci. Rep. 2016, doi: 10.1038/srep27694; (e) Jing, H.; Lin, H., Oncotarget 2016, doi: 10.18632/oncotarget.8502.) and kidney diseases ((a) Zhou, X., et al., Hum. Mol. Genet. 2014, 23, 1644-1655; (b) Ponnusamy, M., et al., J. Pharmacol. Exp. Ther. 2014, 350, 243; (c) Jung, Y. J., et al., J. Am. Soc. Nephroi. 2015, 26, 1549). SIRT2 inhibitors can also be useful for the treatment of sepsis (Zhao, T., et al., Curr. Mol. Med. 2015, 15, 634.) and hepatic fibrosis (Arteaga, M., et al., Am. J. Physiol. Gastrointest. Liver Physiol. 2016, 310, G1155), and for the control of platelet function (Moscardo, A., et al., J. Thromb. Haemost. 2015, 13, 1335).
Currently there is a need for agents that are useful for inhibiting SIRT2. Such agents may be useful to treat pathologies associated with SIRT2, such as, for example, Parkinson's disease.